Compositions and methods for treating glucose-dependent insulinotropic peptide-dependent cushing's syndrome

Abstract

The present invention relates to compositions and methods for treating glucose-dependent insulinotropic peptide (GIP)-dependent Cushing's syndrome using an effective amount of an SGLT1 inhibitor compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. The present invention also encompasses the use of these compounds in the treatment of related disorders, such as pituitary tumors that secrete growth hormone and neuroendocrine tumors that ectopically express GIPR. The SGLT1 inhibitor compounds primarily act in the gut and can be administered in a variety of oral dosage forms, including coated capsules, coated tablets, liquids, powders, and oral disintegrating tablets, in a dosage range of about 0.1 mg / day to about 60 mg / day.

Description

[0001] Cross-referencing related applications This application claims priority to U.S. Provisional Application No. 63 / 605,200, filed December 1, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0002] This invention relates to compositions and methods for treating and improving glucose-dependent insulinotropic peptide (GIP)-dependent Cushing's syndrome. Background Technology

[0003] In patients with primary adrenal Cushing's syndrome (CS), regardless of whether the cause is a unilateral adrenal tumor or bilateral adrenal hyperplasia, excessive cortisol secretion leads to a gradual suppression of the secretion of hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH). ACTH is a major stimulator of the MC2R-Gsα-cAMP-protein kinase A signaling pathway for steroid production in the zona fasciculata cells of the adrenal cortex. However, the mechanism by which cortisol secretion is maintained in the absence of ACTH has remained unclear for the past two decades, until recent review studies have clarified several cellular mechanisms and genetic variations.

[0004] In 1971, Robert L. Ney first proposed the concept of ectopic adrenal membrane receptor expression. Southerland demonstrated that adrenaline activates adenylate cyclase (AC) to produce cAMP, which in turn stimulates phosphorylase and promotes glucose release from the liver, thus establishing the initial mechanism of action of G protein-coupled receptors (GPCRs). Subsequently, Grant W. Liddle suggested that Ney investigate whether ACTH regulates steroid synthesis by modulating cAMP production in the adrenal cortex. In normal rat adrenal cell membrane preparations, only ACTH stimulates AC and promotes cAMP production; however, in the membrane of 494 rat adrenocortical carcinoma cells that produce corticosterone, in addition to ACTH, adrenaline, noradrenaline, and thyroid-stimulating hormone (TSH) also stimulate cAMP production. Further research showed that the analgesic receptors (ACs) in this tumor could also be stimulated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and were mildly stimulated by prostaglandin E1 (PGE1), while glucagon, insulin, vasopressin, parathyroid hormone (PTH), and calcitonin had no such effect. These illicit hormones did not produce additive or synergistic effects, indicating that multiple specific receptors in this tumor activate the same AC. High-affinity β-adrenergic binding sites and AC stimulation were observed in the membrane of rat adrenocortical carcinoma 494 cells, but not in normal adrenal membranes. In one androgen-secreting tumor resected from a CS patient, TSH and ACTH induced AC stimulation, while adrenaline, LH, or glucagon had no such effect; in one of three cortisol-secreting adenomas, ACs were only mildly stimulated by TSH and ACTH. The authors conclude: "The physiological significance of these abnormal tumor responses is currently unclear, and their relationship with tumor function remains to be speculated. However, in some cases, the 'autonomous' behavior of endocrine tumors may not be as genuine as it appears, but rather due to stimulation of the tumor by hormones other than those appropriate from the parent gland." In 1978, Dr. Leslie J. DeGroot of Chicago reported a case of female CS patient secondary to adrenal adenoma: her morning plasma cortisol levels were low and gradually increased during the day; however, the relationship between this change and food intake was not investigated. In retrospect, her "persistent diurnal cortisol secretion rhythm" pattern was likely secondary to food-dependent CS.

[0005] Pavel Hamet first identified “food-dependent” cortisol production in a 41-year-old male patient with cortisol-secreting adenoma and cyclical hormone production. His plasma cortisol levels were consistently low in the morning or on an empty stomach, but rose to high levels postprandially; high-dose oral dexamethasone could not suppress food-induced increases in plasma cortisol. Adenylate cyclase activity in the excised adrenal adenoma membrane preparation was stimulated by ACTH 27% and vasopressin 62%, but not by FSH, glucagon, or Ang-II; the effects of various gastrointestinal hormones were not investigated in this case.

[0006] A 48-year-old French-Canadian woman with primary bilateral macronodular adrenal hyperplasia (PBMAH) presented with significant symptoms of chronic cortisol syndrome (CS) over the past 2-3 years. Notably, her morning fasting plasma cortisol levels were low and fluctuated significantly throughout the day, while plasma ACTH was consistently suppressed. We demonstrated a correlation between food intake and postprandial cortisol peaks, similar to previous cases of food-dependent cortisol-secreting unilateral adenomas. The identification of the central role of gastrointestinal hormones stemmed from the observation that oral administration of 75g glucose or a lipid / protein-rich meal stimulated plasma cortisol, while intravenous glucose did not; furthermore, somatostatin pretreatment inhibited the cortisol-stimulating effect of oral glucose. A review of various gastrointestinal secretagogue hormones showed that only GIP and glucagon-like peptide-1 were equally stimulated by oral glucose and lipids, while protein stimulation was weaker. Plasma cortisol levels correlated with plasma GIP concentrations across different experimental meals. In vivo infusion of GIP to reproduce its physiological postprandial concentration stimulated cortisol production in PBMAH patients, but had no effect on four healthy controls; plasma cortisol in these patients was stimulated by ACTH administration but not by CRH, glucagon, insulin-induced hypoglycemia, pentagastrin, or vasopressin. The hypothesis of the presence of functional ectopic GIP receptors (GIPR) in adrenal tissue was supported by adrenal imaging results following in vivo injection of [123I]-GIP. In vitro incubation of bilaterally resected, dispersed PBMAH adrenal cells confirmed the presence of GIP-mediated cortisol secretion in the patient's cells, which is absent in normal adult or fetal adrenal cells, or other adenomas that secrete cortisol or aldosterone. Following in vitro incubation with secretin, cholecystokinin, vasoactive intestinal peptide (VIP), substance P, scutellarin, calcitonin gene-related peptide, glucagon, vasopressin, atrial natriuretic peptide (ANP), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone (GHRH), neurotensin, or neurokinin A, the patient's adrenal cells did not exhibit cortisol stimulation. Therefore, it is concluded that food-dependent cortisol secretion originates from an abnormal response of adrenal cells to the physiological secretion of GIP; ectopic GIPR expression on adrenal cells may be the cause of this novel CS etiology, but this cannot be confirmed as the receptor has not yet been cloned.

[0007] Cloning rat and human GIPR cDNAs enabled the study of GIPR expression in tissues from these patients. In situ hybridization revealed abundant GIPR mRNA in unilateral adrenal adenoma cells from a patient with GIP-dependent CS; this signal was absent in adenomas from patients with non-GIP-dependent CS but not detected in normal adrenal cortex. Significant adrenal GIPR overexpression was confirmed by RT-PCR amplification in adrenal adenomas and PBMAH tissues from two indicator cases of GIP-dependent CS, compared to normal human pancreas, normal adult or fetal adrenal cortex, or non-GIP-dependent adrenal CS tissues. Low levels of GIPR mRNA were detected in normal fetal and adult adrenal tissues after at least 35 cycles of amplification and hybridization with labeled cDNA, but this mRNA was not effectively coupled to steroid production. Sequence analysis of full-length cDNA from normal and GIP-dependent adrenal glands revealed no GIPR mutations in the affected adrenal tissues; isoforms lacking exons 4 and 9 in similar proportions were identified in both normal adrenal glands and GIP-dependent tumors. Chabre et al. confirmed the presence of the same overexpressed GIPR isoform in GIP-dependent adenomas using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing; GIPR bands were not detected in atrophic adrenal cortex near the tumor or in normal adult adrenal glands. Compared to normal tissues, GIP-dependent adenomas exhibited lower ACTH receptor (MC2R) expression levels.

[0008] Studies have confirmed that GIP receptors can be ectopically overexpressed in other tissues. Umahara first proposed in 2003 that some patients with acromegaly exhibit anomalous increases in growth hormone (GH) levels after oral glucose administration, indicating the expression of a functional GIP / GIPR axis. In four acromegaly patients, two showed elevated plasma GH levels after oral (but not intravenous) glucose loading; while patients who only showed anomalous responses to oral glucose required intravenous GIP infusion to replicate similar increases. Both responses disappeared after pituitary tumor resection. Two subsequent independent studies identified higher GIPR expression levels in approximately 30% of growth hormone-secreting pituitary adenomas (GH-PAs), associated with anomalous GH increases after oral glucose administration, consistently limited to GNAS1 gene mutation-negative cases. Following GIP stimulation, most primary cultures derived from GIPR-expressing growth hormone-secreting adenomas also induced GH secretion. At diagnosis, GIPR-positive patients (32%) had a significantly higher proportion of males and higher serum IGF-1 levels. Abnormally elevated GH levels were significantly associated with a lower likelihood of hyperprolactinemia, a more mild tumor phenotype (smaller, less aggressive tumors), and a better response to first-generation somatostatin analogues (SSA).

[0009] Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, varying in their origin, hormone secretion, and clinical presentation. NETs commonly exhibit overexpression of multiple hormone receptors, a phenotype that makes them highly valuable for diagnosis, imaging, and treatment. Among these receptors, the somatostatin receptor (SSTR) has become a broad target. Specific ligands in NETs are used to locate primary and metastatic lesions, resulting in symptom improvement, tumor shrinkage, or disease stabilization in approximately 50% of patients. Currently, research on glucose-dependent insulinotropic peptide receptor (GLP1R) in NETs is increasing, particularly for tumors expressing little or no SSTR and / or GLP1R (such as insulinomas and undifferentiated NETs). Waser et al. examined 260 human tumor samples using in vitro receptor autoradiography and reported that in various predominantly SSTR-negative gastrointestinal and bronchial NETs, ​​GIPR showed a homogeneous and strong distribution with a high tumor-to-normal tissue ratio (T / N ratio). Two other studies confirmed the upregulation of GIPR expression in pancreatic, small intestinal (SI-), and gastric and duodenal (GD-) NETs; hypermethylation of GIPR was observed in 74% of small intestinal neuroendocrine tumors (SINETs), and elevated GIPR expression was positively correlated with the occurrence of liver metastases. Similar high T / N ratios of GIPR were also observed in nearly 80% of medullary thyroid carcinoma cases (especially larger sporadic advanced cases); in vitro, GIP was coupled with calcitonin secretion.

[0010] Subtypes of SGLT include SGLT1, which is primarily expressed in the small intestine, and SGLT2, which is expressed in the proximal tubules of the kidney. They are responsible for glucose absorption in the small intestine and glucose reabsorption in the proximal tubules, respectively. U.S. Patent No. 7,635,684 (in whole, by reference) describes compounds with inhibitory activity against human SGLT1; U.S. Patent No. 9,200,025 (in whole, by reference) describes potent inhibitors of SGLT1, particularly selective inhibitors of SGLT1 and specific inhibitors that are systemically exposed and act locally in the intestine; the disclosure of U.S. Patent No. 11,596,644, by evaluating the cellular uptake of radiolabeled methyl-α-D-glucopyranoside (α-MG) in vitro, confirms that mizaggliflozin is selective for SGLT1 compared to SGLT2.

[0011] Mizaggliflozin (3-(3-{4-[3-(β-D-glucopyranoyl)-5-isopropyl-1H-pyrazole-4-methyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide) is an SGLT1 inhibitor developed by Kissei Pharmaceutical Co., Ltd. Currently, no SGLT1 inhibitors have been approved. Mizaggliflozin selectively inhibits SGLT1, thereby inhibiting the secretion of gastrointestinal inhibitory peptide 1 (GIP-1)—a known insulin secretagogue—from the digestive tract. When less unabsorbed glucose is present, the likelihood of gastrointestinal symptoms is lower.

[0012] Because enhanced SGLT1 activity in the small intestine is thought to promote insulin secretagogue production, there has been a need to develop agents with potent inhibitory activity against human SGLT1 for the prevention or treatment of diabetes. See, for example, US Patent No. 8,324,176. Crystalline compounds of miszaggliflozin have been described for the prevention or treatment of diseases associated with hyperglycemia, such as diabetes, impaired glucose tolerance, abnormal fasting blood glucose, diabetic complications, or obesity, as well as diseases associated with elevated blood galactose levels, such as galactosemia. US Patent No. 8,399,418 describes miszaggliflozin monosaccharide; US Patent No. 8,354,382 describes miszaggliflozin hemifumarate dehydrated salt; and US Patent No. 11,596,644 describes the use of miszaggliflozin in the treatment of hypoglycemia after bariatric surgery. Summary of the Invention

[0013] The methods and compositions described in accordance with the principles and exemplary embodiments of the present invention can be used to treat GIP-dependent Cushing's syndrome in subjects in need.

[0014] According to one aspect of the invention, a method for treating a subject with GIP-dependent Cushing's syndrome includes orally administering to the subject an effective amount of an SGLT1 inhibitor compound of formula I or II, or an effective amount of a pharmaceutically acceptable salt of an SGLT1 inhibitor compound of formula I or II.

[0015] The compound of formula I is:

[0016] Formula I; in R1 is H or C with optional substitution. 1-6 alkyl; One of Q and T is a functional group: or , The other one is C. 1-6 Alkyl, halogenated (C1-6 Alkyl), C 1-6 Alkoxy-substituted (C 1-6 alkyl) or C 3-7 cycloalkyl; R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, Halogenated (C 1-6 Alkyl), halogenated (C) 1-6 alkoxy), C 1-6 Alkoxy-substituted (C 1-6 alkoxy), C 3-7 Cycloalkyl-substituted (C 2-6 alkoxy) or -AR A Where A is a single bond, oxygen atom, methylene, ethylene, -OCH2- or -CH2O-; and R A C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, or heteroaryl, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups, halogenated (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), carboxyl, C 2-7 Alkoxycarbonyl, cyano, and nitro or heteroaryl; the heteroaryl group may have substituents selected from halogen atoms and C. 1-6 alkyl; X is a single bond, an oxygen atom, or a sulfur atom; Y is a C that can be substituted with a hydroxyl group. 1-6 Alkylene or C 2-6 alkenyl; Z is -R B -COR C -SO2R C -CON(R) D )R E -SO2NHR F or -C(═NR) G )N(R H )R I ;R C It is aryl, heteroaryl or C 1-6 Alkyl groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl; the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i); R4, R B R D R E and R F Whether they are the same or different, each is a hydrogen atom, aryl, heteroaryl, or C atom. 1-6 Alkyl group; wherein the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C64 groups, and C44 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i), or R4 and R B Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl, or R D and R E Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl; R G R H and R I Whether they are the same or different, each consists of a hydrogen atom, a cyano group, a carbamoyl group, and a C atom. 2-7 Acyl group, C 2-7 Alkoxycarbonyl, aryl (C 2-7 Alkoxycarbonyl), nitro, C 1-6 alkylsulfonyl, sulfonamide, carbamimidoyl, or C 1-6 Alkyl, the C 1-6The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i), or R G and R H The two combine to form ethylene, or R H and R I Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl; R3, R5, and R6 may be the same or different, each consisting of a hydrogen atom, a halogen atom, or a carbon atom. 1-6 Alkyl or C 1–6 alkoxy groups; and The substituent group (i) consists of hydroxyl, C 1-6 Alkoxy, C 1-6 Alkylthio, amino, mono(C) 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C) 1-6 [alkyl]amino, urea, sulfonamide, mono(C 1-6 alkyl)urea or di(C) 1-6 Alkyl)urea, mono(C) 1-6 alkyl)sulfonamide or di(C) 1-6 alkyl)sulfonamide group, C 2-7 Acylamino, C 1-6 Alkylsulfonamide, C 1-6 alkylsulfonyl, carboxyl, C 2-7 Alkoxycarbonyl, -CON(R) J )R K Composition, wherein R J With R K They may be the same or different, and each is a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may have one to three identical or different substituents, said substituents being selected from hydroxyl, amino, mono(C) groups. 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C) 1-6 Alkyl)]amino, urea, mono(C) 1-6 alkyl)urea or di(C) 1-6 Alkyl) urea, C 2-7Acylamino, C 1-6 alkylsulfonylamino and carbamoyl, or R J With R K The two combine with the adjacent nitrogen atom to form C. 2-6 Cyclic amino, aryl (C 1-6 alkoxy), aryl (C 1-6 alkylthio), C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, heteroaryl, C 2-6 Cyclic amino or C 1-4 Aromatic cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl, the aryl (C 1-6 The alkoxy group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 alkoxy, the aryl (C 1-6 The alkylthio group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl and C 1-6 alkoxy groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl, the C 1-4 Aromatic cyclic amino groups may have C 1-6 Alkyl groups as substituents; The compound represented by formula II is:

[0017] Formula II in R7 is hydrogen, and C is optionally substituted. 1-10 Alkyl, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution is by one or more R 7A Replace; each R 7A The C group is independently an amino, ester, amide, thiol, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution is by one or more R 7B Replace; each R 7B Independently for C 1-4 Alkyl, halogen, or hydroxyl; n is 0, 1, or 2; Each R8 is independently F or OR 8A , where each R 8A Independently hydrogen, C 1-4 Alkyl or acyl groups; Each R9 is independently a halogenated, hydroxyl-containing, or optionally substituted C-type. 1-10 Alkyl or C 1-10 alkoxy, wherein the optional substitution is by one or more R 9A Replace; each R 9A C is independently an amino, ester, amide, mercapto, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution is by one or more R 9B Replace; each R 9B Independently for C 1-4 Alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; Each R 10 Independently for R 10A -N(R) 10A (R) 10B -OR 10A -SR 10A -S(O)R 10A or -S(O)2R 10A ;R 10A C is an optional replacement 4-20 Alkyl or 4-20 heteroalkyl, wherein the optional substitution is by one or more R 10C Replace, and R 10C Optional connection to another R 10A Partially forming dimers or trimers; R 10B For hydrogen or R 10A ; Each R 10CIndependently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidinyl, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitro, nitrosyl, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thionyl, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein X1, X2, and X3 are each independently substituted C with optional substitution. 1-4 Alkyl, C 1-6 Cycloalkyl, 5- or 6-membered heterocyclic or aryl; the optional substitution is by one or more R 10D Substitution, L1 and L2 are each independently optional substitutions of C. 1-6 Alkyl or 1-10 heteroalkyl, wherein the optional substitution is by one or more R 10E replace; Each R 10D Independently for R 10E Or by one or more R 10E Optional substitution of C 1-6 alkyl; Each R 10E Independently, m is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, thioaldehyde, thiocyanate, thioketone, or urea group; and m is 1, 2, or 3; and The SGLT1 inhibitor compound described therein has a major pharmacological site of action in the intestine of the subject.

[0018] The method is used to treat GIP-dependent Cushing's syndrome, and includes, but is not limited to: growth hormone (GH)-secreting pituitary tumors that ectopically express GIPR, neuroendocrine tumors that ectopically express GIPR, or any organ or tissue that ectopically expresses GIPR.

[0019] The method described in this invention can use a variety of SGLT1 inhibitor compounds, including but not limited to: , , , , and .

[0020] According to the present invention, the dosage of the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof may be from about 0.1 mg / day to about 60 mg / day, but is not limited to this dosage range.

[0021] In another aspect of the invention, the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered before a meal. Attached Figure Description

[0022] Figure 1 The study shows GLP-1 and GIP levels in patients with hypoglycemia following bariatric surgery after a single oral dose of 2.5 mg, 5.0 mg, and 10 mg of mitazaggliflozin. Detailed Implementation

[0023] This invention relates to methods and compositions for treating GIP-dependent Cushing's syndrome. Specifically, the method of this invention relates to treating a subject with GIP-dependent Cushing's syndrome, comprising orally administering to the subject an SGLT1 inhibitor compound of formula I or II, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is:

[0024] in R1 is H or C with optional substitution. 1-6 alkyl; One of Q and T is a functional group: or , The other one is C. 1-6 Alkyl, halogenated (C 1-6 Alkyl), C 1-6 Alkoxy-substituted (C 1-6 alkyl) or C 3-7 cycloalkyl; R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, Halogenated (C 1-6 Alkyl), halogenated (C) 1-6 alkoxy), C 1-6 Alkoxy-substituted (C 1-6 alkoxy), C 3-7 Cycloalkyl-substituted (C 2-6 alkoxy) or -AR A Where A is a single bond, oxygen atom, methylene, ethylene, -OCH2- or -CH2O-; and R A C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, or heteroaryl, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyl groups, halogenated (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), carboxyl, C 2-7 Alkoxycarbonyl, cyano, and nitro or heteroaryl; the heteroaryl group may have substituents selected from halogen atoms and C. 1-6 alkyl; X is a single bond, an oxygen atom, or a sulfur atom; Y is a C that can be substituted with a hydroxyl group. 1-6 Alkylene or C 2-6 alkenyl; Z is -R B -COR C -SO2R C -CON(R) D )R E -SO2NHR F or -C(═NR) G )N(R H )R I ;R C It is aryl, heteroaryl or C 1-6 Alkyl groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl; the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i); R4, R B R D R E and R F Whether they are the same or different, each is a hydrogen atom, aryl, heteroaryl, or C atom. 1-6 Alkyl group; wherein the aryl group may have 1 to 3 identical or different substituents, the substituents being selected from halogen atoms, hydroxyl groups, amino groups, C64 groups, and C44 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i), or R4 and R B Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, wherein the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C...1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl, or R D and R E Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, wherein the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl; R G R H and R I Whether they are the same or different, each consists of a hydrogen atom, a cyano group, a carbamoyl group, and a C atom. 2-7 Acyl group, C 2-7 Alkoxycarbonyl, aryl (C 2-7 Alkoxycarbonyl), nitro, C 1-6 alkylsulfonyl, sulfonamide, formamidinyl or C 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i), or R G and R H The two combine to form ethylene, or R H and R I Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl; R3, R5, and R6 may be the same or different, each consisting of a hydrogen atom, a halogen atom, or a carbon atom. 1-6 Alkyl or C 1–6 alkoxy groups; and The substituent group (i) consists of hydroxyl, C 1-6 Alkoxy, C 1-6 Alkylthio, amino, mono(C) 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C)1-6 [alkyl]amino, urea, sulfonamide, mono(C 1-6 alkyl)urea or di(C) 1-6 Alkyl)urea, mono(C) 1-6 alkyl)sulfonamide or di(C) 1-6 alkyl)sulfonamide group, C 2-7 Acylamino, C 1-6 Alkylsulfonamide, C 1-6 alkylsulfonyl, carboxyl, C 2-7 Alkoxycarbonyl, -CON(R) J )R K Composition, wherein R J With R K They may be the same or different, and each represents a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may have one to three identical or different substituents, said substituents being selected from hydroxyl, amino, mono(C) groups. 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C) 1-6 Alkyl)]amino, urea, mono(C) 1-6 alkyl)urea or di(C) 1-6 Alkyl) urea, C 2-7 Acylamino, C 1-6 alkylsulfonylamino and carbamoyl, or R J With R K It combines with adjacent nitrogen atoms to form C 2-6 Cyclic amino, aryl (C 1-6 alkoxy), aryl (C 1-6 alkylthio), C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, heteroaryl, C 2-6 Cyclic amino and C 1-4 Aromatic cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl groups and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl, the aryl (C 1-6 The alkoxy group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 alkoxy, the aryl (C 1-6The alkylthio group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl and C 1-6 alkoxy groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), C 1-6 alkylsulfonamide-substituted C 1-6 Alkyl, the C 1-4 Aromatic cyclic amino groups may have C 1-6 Alkyl groups as substituents; The compound represented by formula II is:

[0025] Formula II in R7 is hydrogen, and C is optionally substituted. 1-10 Alkyl, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution is by one or more R 7A Replace; each R 7A C is independently an amino, ester, amide, mercapto, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution is by one or more R 7B Replace; each R 7B Independent as C 1-4 Alkyl, halogen, or hydroxyl; n is 0, 1, or 2; Each R8 is independently F or OR 8A , where each R 8A Independently hydrogen, C 1-4 Alkyl or acyl groups; Each R9 is independently a halogenated, hydroxyl-containing, or optionally substituted C-type. 1-10 Alkyl or C 1-10 alkoxy, wherein the optional substitution is by one or more R 9A Replace; each R 9AC is independently an amino, ester, amide, mercapto, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, C 1-5 cycloalkyl or five-membered heterocycle, wherein the optional substitution site is occupied by one or more R 9B Replace; each R 9B Independently for C 1-4 Alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; Each R 10 Independently for R 10A -N(R) 10A (R) 10B -OR 10A -SR 10A -S(O)R 10A or -S(O)2R 10A ;R 10A C is an optional replacement 4-20 Alkyl or 4-20 heteroalkyl, wherein the optional substitution is by one or more R 10C Replace, and R 10C Optional connection to another R 10A Partially forming dimers or trimers; R 10B For hydrogen or R 10A ; Each R 10C Independently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thioalkyl, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thioketone, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein X1, X2, and X3 are each independently substituted C with optional substitution. 1-4 Alkyl, C 1-6 Cycloalkyl, 5- or 6-membered heterocyclic or aryl; the optional substitution is by one or more R 10D The substitutions for L1 and L2 are each an optional substitution of C. 1-6 Alkyl or 1-10 heteroalkyl, wherein the optional substitution is by one or more R 10E Replace; each R 10D Independently for R 10E Or by one or more R 10E Optional substitution of C 1-6 Alkyl; each R 10EIndependently, it can be amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, or isothiocyanate. It can also be nitrile, nitro, nitroso, nitoxy, oxo, thioalkyl, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thionyl, or urea; and m is 1, 2, or 3; and The SGLT1 inhibitor compounds described herein have a major pharmacological site of action in the intestine of the subject. Therefore, the SGLT1 inhibitor compounds represented by Formula I or Formula II inhibit SGLT1 activity in the intestine of the subject. Thus, the SGLT1 inhibitor compounds represented by Formula I or Formula II exhibit local action in the intestine and have low systemic exposure. Specific locally acting compounds, when orally administered to mice, rats, or humans at a dose of 10 mg / kg, have maximum plasma concentrations (Cmax) below 250 nM, 100 nM, 50 nM, or 10 nM, respectively. Systemic exposure (such as Cmax) can be determined by methods well known in the art, including liquid chromatography-mass spectrometry. For example, after oral administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg doses of mizaggliflozin to fasted male rats, the drug exposure, the observed maximum concentration (Cmax), and the area under the plasma concentration-time curve (AUCt) from zero to the last measurable concentration all increased with increasing dose, but no clear dose-proportional relationship was observed. The oral bioavailability of misazaglipine in rats is extremely low (ranging from 0.01% to 0.08%). After oral administration, most of misazaglipine remains in the intestine and is almost entirely excreted in feces (>97% of the oral dose in rats and >82% of the oral dose in non-human primates).

[0026] "Pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases as well as organic acids and bases. Applicable pharmaceutically acceptable base addition salts include, but are not limited to: metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc; or organic salts formed from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. Applicable non-toxic acids include, but are not limited to: inorganic and organic acids, such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furanoic acid, galacturonic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Typical examples of salts therefore include hydrochloride and mesylate; other common types in the art can be found in Remington's Pharmaceutical Sciences, 18th edition (McKay Publishers, Easton, PA: 1990) and Remington: The Science and Practice of Pharmacy, 19th edition (McKay Publishers, Easton, PA: 1995).

[0027] Unless otherwise stated, a "therapeuticly effective amount" of a compound means an amount sufficient to produce a therapeutic effect in the treatment or management of a disease or condition, or to delay or alleviate one or more symptoms associated with that disease or condition. A "therapeuticly effective amount" of a compound means the amount at which the therapeutic agent, used alone or in combination with other therapies, provides therapeutic benefit in the treatment or management of a disease or condition. The term "therapeuticly effective amount" may also encompass amounts that improve overall therapeutic efficacy, alleviate or prevent symptoms and triggers of a disease or condition, or enhance the efficacy of additional treatments.

[0028] The terms “treat,” “treating,” and “treatment” refer to actions taken when a patient has a specific disease or condition that reduce the severity of the disease or condition or slow down its progression.

[0029] The term "subject" refers to a human or animal patient who requires treatment for glucose-dependent insulinotropic peptide (GIP)-dependent Cushing's syndrome and related conditions. This includes humans or animals diagnosed with GIP-dependent Cushing's syndrome, growth hormone-secreting pituitary tumors, neuroendocrine tumors that ectopically express GIPR, or any organ or tissue that ectopically expresses GIPR.

[0030] It should also be noted that if the stereochemical configuration of a structure or part thereof is not indicated using bold or dashed lines, then the structure or part thereof should be considered to include all its stereoisomers. Furthermore, atoms in the diagram showing unsatisfied valence states are assumed to be bonded to a sufficient number of hydrogen atoms to satisfy the valence state requirement. Additionally, if the valence state allows, chemical bonds represented by a solid line parallel to the dashed line encompass both single and double bonds (such as aromatic bonds).

[0031] In some embodiments, the present invention relates to the treatment of GIP-dependent Cushing's syndrome, and includes, but is not limited to: growth hormone-secreting pituitary tumors that ectopically express GIPR, neuroendocrine tumors that ectopically express GIPR, or any organ or tissue that ectopically expresses GIPR.

[0032] For the methods described in this invention, the SGLT1 inhibitors shown in Formulas I and II can be prepared by methods known in the art. See, for example, U.S. Patent Nos. 7,635,684 and 9,200,025.

[0033] In a preferred method of the present invention, the SGLT1 inhibitors represented by Formula I and Formula II are selected from the following: , , , .

[0034] In some preferred methods of the present invention, the SGLT1 inhibitor is selected from LX2671 and mizaggliflozin. In a more preferred method of the present invention, the SGLT1 inhibitor is mizaggliflozin, namely 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl-]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide, which can be converted into a pharmaceutically acceptable salt according to methods known in the art. Examples of such salts include, for instance, acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; acid addition salts formed with organic acids, such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, etc.; salts formed with inorganic bases, such as sodium salts, potassium salts, etc.; and salts formed with organic bases, such as N-methyl-D-glucosamine, N,N'-dibenzylethylenediamine, 2-aminoethanol, tris(hydroxymethyl)aminomethane, arginine, lysine, etc.

[0035] In some methods of using mizaggliflozin in this invention, the pharmaceutical salt is selected from monosaccharide and hemifumaric acid dehydrates. The mizaggliflozin hemifumaric acid dihydrate in U.S. Patent No. 8,354,382 is shown below: .

[0036] The mirtazolidin monosaccharide in US Patent No. 8399418 is shown below: .

[0037] In one method of the present invention, the dosage of the SGLT inhibitor compound represented by Formula I or Formula II is from about 0.1 mg / day to about 160 mg / day. For example, the dosage is 0.1 mg / day, 0.2 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 3 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, or 160 mg / day. Preferably, the dosage is from about 1 mg / day to about 60 mg / day. For example, the dosage is 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 24 mg / day, 27 mg / day, 30 mg / day, 33 mg / day, 36 mg / day, 39 mg / day, 42 mg / day, 45 mg / day, 48 mg / day, 51 mg / day, 54 mg / day, 57 mg / day, or 60 mg / day. In some methods of the present invention, the SGLT inhibitor compound represented by Formula I or Formula II is administered as a pharmaceutically acceptable salt. In the above methods, the daily dose refers to the compound in mg / day. The effective therapeutic dose of the medication shall be determined by the treating physician.

[0038] The daily dose may be divided into one or more dose units, such as two, three, or four unit doses administered daily. A unit dose refers to the amount of compound administered in a single dose. In the preferred method of the invention, the SGLT inhibitor compound represented by Formula I or Formula II is administered three times daily at a unit dose of about 0.1 mg to about 20 mg. For example, the dosage is 0.1 mg / time, three times daily; 0.2 mg / time, three times daily; 0.5 mg / time, three times daily; 1 mg / time, three times daily; 2 mg / time, three times daily; 3 mg / time, three times daily; 4 mg / time, three times daily; 5 mg / time, three times daily; 6 mg / time, three times daily; 7 mg / time, three times daily; 8 mg / time, three times daily; 9 mg / time, three times daily; 10 mg / time, three times daily; 11 mg / time, three times daily; 12 mg / time, three times daily; 13 mg / time, three times daily; 14 mg / time, three times daily; 15 mg / time, three times daily; 16 mg / time, three times daily; 17 mg / time, three times daily; 18 mg / time, three times daily; 19 mg / time, three times daily; or 20 mg / time, three times daily. In some methods of the present invention, the SGLT inhibitor compound represented by Formula I or Formula II is administered as a pharmaceutically acceptable salt. In such methods, the unit dose refers to the compound in mg.

[0039] In a preferred method of the present invention, the SGLT inhibitor compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, is administered before meals. For example, the SGLT inhibitor compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, is administered once daily before breakfast, lunch, and dinner.

[0040] According to the method of the present invention, pharmaceutical compositions of SGLT1 inhibitor compounds of Formula I or Formula II, or pharmaceutically acceptable salts thereof, are used in different dosage forms depending on their intended use. Examples of oral dosage forms include powders, granules, fine granules, dry syrups, tablets, crushed tablets, chewable tablets, instant tablets, multilayer compressed tablets, uncoated tablets, enteric-coated tablets, capsules, etc. Enteric-coated tablets are tablets made by coating a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coating materials include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Multilayer compressed tablets are tablets made through one or more compression cycles, including laminated tablets, compressed coated tablets, and dry-coated tablets. Tablets may also employ microencapsulation technology to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. Pharmaceutical compositions of SGLT1 inhibitor compounds shown in Formula I or Formula II also include sustained-release formulations, including gastrointestinal mucosal adhesive formulations (e.g., International Patent Nos. WO99 / 10010, WO99 / 26606 and Japanese Patent Publication No. 2001-2567).

[0041] The pharmaceutical composition can be prepared by mixing or diluting with suitable pharmaceutical additives (such as excipients, disintegrants, binders, fillers, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, dissolution promoters, etc.) and then formulating the mixture according to conventional methods. When using the SGLT1 inhibitor compound represented by Formula I or Formula II in combination with a non-SGLT1 inhibitor drug, the active ingredients can be formulated individually or together.

[0042] Some compositions of the present invention can be formulated into oral dosage forms. For example, oral dosage forms of the present invention may be tablets containing 2.5 mg, 5 mg, and 10 mg doses of mizaggliflozin. In one embodiment, the tablets of the present invention are white to slightly yellowish-white film-coated tablets, oval in shape, measuring 8 mm × 4.5 mm. In some embodiments, the qualitative composition of the tablet excipients may include one or more excipients shown in Table 1. The tablets of the present invention are typically stored in a sealed container system.

[0043] Table 1

[0044] In some embodiments of the present invention, the oral dosage form of mizaggliflozin is a capsule. Table 2 shows exemplary capsule compositions.

[0045] Table 2

[0046] In some methods of the present invention, an SGLT1 inhibitor compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is administered in combination with at least one glucagon-like peptide (GLP)-1 receptor antagonist. Preferably, the GLP-1 receptor antagonist is a peptide fragment of exenatide (exendin 9-39). In the methods of the present invention, when an SGLT1 inhibitor compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is administered in combination with such a drug, the dose of the SGLT1 inhibitor compound of Formula I or II may be reduced according to the dose of the GLP-1 receptor antagonist.

[0047] Example Example 1: Human Single-Dose Study A placebo-controlled, randomized, double-blind study was conducted on healthy adult male volunteers who received single oral doses of 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg of mizaggliflozin. The single dose was administered orally with approximately 200 mL of water immediately before breakfast, after fasting for at least 10 hours. Pharmacodynamic parameters (blood glucose levels, insulin, GLP-1, and gastric inhibitory peptide (GIP)) were measured as shown in Tables 3 to 6. Drug concentrations were recorded at each time point, and the summative statistic and coefficient of variation (CV) of AUC0-t were calculated at a maximum of 6 hours after administration. Time points included before administration and at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours after administration. The inhibitory effect on postprandial hyperglycemia was preliminarily assessed by measuring blood glucose and insulin levels. The effect on secretin secretion was preliminarily assessed by measuring GLP-1 and GIP levels.

[0048] Table 3

[0049] Regarding the effect of misazaglilin on incretin secretion, it was shown that misazaglilin inhibited GIP secretion (see Table 6). The area under the curve (AUC) for GIP was low in all misazaglilin groups, indicating that GIP secretion was suppressed. GIP concentrations peaked more than 3 hours after treatment. No definitive conclusions were reached regarding its effect on GLP-1 (Table 5). GLP-1 levels were high in all misazaglilin treatment groups, but changes in GLP-1 could not be assessed due to the large inter-subject mean baseline variability (1.9–9.9 pmol*h / L).

[0050]

[0051] Example 2: Human Repeated Dosing Study A randomized, placebo-controlled, parallel-group, double-blind comparative study was conducted on healthy adult male volunteers who received three daily oral doses of mizaggliflozin 2 mg, 5 mg, 10 mg, or 20 mg, or placebo, or migliflozin (50 mg each time). The oral dosage was as follows: on days 1 and 13, one dose was administered immediately before breakfast with approximately 150 mL of water; from days 3 to 12, three doses were administered immediately before each meal.

[0052] The changes and ΔAUC values ​​of the following parameters from 0 to t* hours after breakfast, lunch and dinner were measured: blood glucose level, serum insulin concentration, blood active GLP-1 concentration and blood total GIP concentration, where t = 0.5, 1, 1.5, 2 and 3 (t = 0.5, 1, 1.5, 2, 3 and 5 were measured only after breakfast), as shown in Tables 7, 8, 9 and 10, respectively.

[0053] Compared with the placebo group, the miglitol group effectively suppressed hyperglycemia after breakfast, lunch, and dinner. Furthermore, inhibition of insulin secretion, suppression of hyperglycemia, increased total GLP-1 concentration, a trend towards increased active GLP-1 concentration, and suppressed increases in total GIP concentration were observed. The mizaggliflozin group showed comparable levels of hyperglycemia suppression after breakfast, lunch, and dinner to the miglitol group. Insulin secretion suppression and hyperglycemia suppression in the mizaggliflozin group were consistent with those in the miglitol group. The level of increase in total GLP-1 concentration in the mizaggliflozin group was comparable to that in the miglitol group. The trend towards increased active GLP-1 concentration in the mizaggliflozin group was similar to that in the miglitol group. The level of decrease in total GIP concentration in the mizaggliflozin group was comparable to that in the miglitol group. These pharmacodynamic effects were substantially persistent during the 10-day repeated-dose period. There was no correlation between plasma mizaggliflozin concentration and pharmacodynamic effects. Measurements in Tables 7 through 10 were taken on day 3 after breakfast.

[0054]

[0055]

[0056] Example 3: Single-dose study in patients with hypoglycemia after bariatric surgery A randomized, open-label study was conducted to administer single oral doses of 2.5 mg, 5.0 mg, and 10 mg of misazaglipine to patients with post-barbiturate hypoglycemia. The single dose was administered orally (with approximately 50 mL of water) approximately 20 minutes before a mixed meal tolerance test (MMTT) after fasting for at least 8 hours. Pharmacodynamic parameters (blood glucose levels, insulin, GLP-1, and glucose-dependent insulinotropic peptide (GIP)) were measured. Concentrations were measured at each time point, and the summative statistic and coefficient of variation (CV) of AUC0-t were calculated up to 6 hours after administration. Time points were: before administration and at 5, 10, 20, 40, 60, 80, 100, 120, 150, 180, 240, and 360 minutes after the start of the MMTT. The inhibitory effect on postprandial hyperglycemia was preliminarily assessed by measuring blood glucose and insulin levels. The effect on incretin secretion was preliminarily assessed by measuring GLP-1 and GIP. See Tables 11 and 12. Figure 1 .

[0057]

Claims

1. A method for treating a subject with glucose-dependent insulinotropic peptide (GIP)-dependent Cushing's syndrome, comprising orally administering to the subject an effective amount of an SGLT1 inhibitor compound of formula I or II, or orally administering to the subject an effective amount of a pharmaceutically acceptable salt of an SGLT1 inhibitor compound of formula I or II; wherein the compound of formula I is: Formula I; in R1 is H or C with optional substitution. 1-6 alkyl; One of Q and T is a functional group: or , And the other of Q or T is C. 1-6 Alkyl, halogenated (C 1-6 Alkyl), C 1-6 Alkoxy-substituted (C 1-6 alkyl) or C 3-7 cycloalkyl; R2 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon atom. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, Halogenated (C 1-6 Alkyl), halogenated (C) 1-6 alkoxy), C 1-6 Alkoxy-substituted (C 1-6 alkoxy), C 3-7 Cycloalkyl-substituted (C 2-6 alkoxy) or -AR A , Where A is a single bond, oxygen atom, methylene, ethylene, -OCH2-, or -CH2O-. R A C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, or heteroaryl, wherein the aryl group has 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups, halogenated (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), carboxyl, C 2-7 Alkoxycarbonyl, cyano, and nitro or heteroaryl; said heteroaryl group has substituents selected from halogen atoms and C. 1-6 alkyl; X is a single bond, an oxygen atom, or a sulfur atom; Y is a C that can be substituted with a hydroxyl group. 1-6 Alkylene or C 2-6 alkenyl; Z is -R B -COR C -SO2R C -CON(R) D )R E -SO2NHR F or -C(═NR) G )N(R H )R I , Where R C It is aryl, heteroaryl or C 1-6 Alkyl groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, C6 groups, and C7 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy; the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl; the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from substituent group (i), wherein the substituent group (i) consists of a hydroxyl group, a C-shaped substituent, ... 1-6 Alkoxy, C 1-6 Alkylthio, amino, mono(C) 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C) 1-6 [alkyl]amino, urea, sulfonamide, mono(C 1-6 alkyl)urea or di(C) 1-6 Alkyl)urea, mono(C) 1-6 alkyl)sulfonamide or di(C) 1-6 alkyl)sulfonamide group, C 2-7 Acylamino, C 1-6 Alkylsulfonamide, C 1-6 alkylsulfonyl, carboxyl, C 2-7 Alkoxycarbonyl, -CON(R) J )R K composition, Where R J With R K Same or different, and R J With R K Each represents a hydrogen atom or a carbon atom. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may have one to three identical or different substituents, said substituents being selected from hydroxyl, amino, mono(C) groups. 1-6 alkyl)amino or di(C) 1-6 alkyl)amino, mono[hydroxy(C 1-6 alkyl)]amino or di[hydroxy(C) 1-6 Alkyl)]amino, urea, mono(C) 1-6 alkyl)urea or di(C) 1-6 Alkyl) urea, C 2-7 Acylamino, C 1-6 Alkylsulfonylamino and carbamoyl; Or R J With R K Together they combine with adjacent nitrogen atoms to form C 2-6 Cyclic amino, aryl (C 1-6 alkoxy), aryl (C 1-6 alkylthio), C 3-7 cycloalkyl, C 2-6 Heterocyclic alkyl, aryl, heteroaryl, C 2-6 Cyclic amino and C 1-4 Aromatic cyclic amino groups, The C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl, The aryl (C) 1-6 The alkoxy group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl and C 1-6 Alkoxy The aryl (C) 1-6 The alkylthio group may have 1 to 3 identical or different substituents on the ring, said substituents being selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkyl and C 1-6 Alkoxy The aryl group may have 1 to 3 identical or different substituents, wherein the substituents are selected from halogen atoms, hydroxyl groups, amino groups, and C atoms. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 Alkoxy The heteroaryl group may have substituents, which are selected from halogen atoms, amino groups, and C atoms. 1-6 alkyl, The C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl), C 1-6 alkylsulfonamide-substituted C 1-6 alkyl, The C 1-4 Aromatic cyclic amino groups may have C 1-6 Alkyl groups as substituents R4, R B R D R E and R F They can be the same or different, each consisting of a hydrogen atom, an aryl group, a heteroaryl group, or a carbon atom. 1-6 Alkyl groups, wherein the aryl group may have 1 to 3 identical or different substituents selected from halogen atoms, hydroxyl groups, amino groups, and C6 groups. 1-6 Alkylsulfonamide, C 1-6 Alkyl and C 1-6 alkoxy groups, wherein the heteroaryl group may have substituents selected from halogen atoms, amino groups, and C atoms. 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the substituent group (i). Or R4 and R B Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl, Or R D and R E Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, wherein the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl; R G R H and R I Whether they are the same or different, each consists of a hydrogen atom, a cyano group, a carbamoyl group, and a C atom. 2-7 Acyl group, C 2-7 Alkoxycarbonyl, aryl (C 2-7 Alkoxycarbonyl), nitro, C 1-6 alkylsulfonyl, sulfonamide, formamidinyl or C 1-6 Alkyl, the C 1-6 The alkyl group may have 1 to 5 identical or different groups selected from the following substituent group (i), Or R G and R H The two combine to form ethylene. Or R H and R I Together with the adjacent nitrogen atom, they form C 2-6 Cyclic amino, the C 2-6 Cyclic amino groups may have substituents selected from hydroxyl, carbamoyl, C... 1-6 Alkyl, oxo, carbamoyl (C 1-6 Alkyl), hydroxyl (C) 1-6 Alkyl) and C 1-6 alkylsulfonamide-substituted C 1-6 alkyl; R3, R5, and R6 may be the same or different, each consisting of a hydrogen atom, a halogen atom, or a carbon atom. 1-6 Alkyl or C 1–6 Alkoxy; The compound represented by formula II is: Formula II in R7 is hydrogen, and C is optionally substituted. 1-10 Alkyl, optionally substituted C 1-5 A cycloalkyl or optionally substituted five-membered heterocycle, wherein C 1-10 Alkyl, C 1-5 Each optional substitution of the cycloalkyl group and the five-membered heterocycle is by one or more R 7A Replace, where each R 7A Independently, it can be an amino, ester, amide, mercapto, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, optional substituted C 1-5 Cycloalkyl and optionally substituted five-membered heterocycles, wherein R 7A Each optional substitution bit is replaced by one or more R 7B Replace, where each R 7B Independently for C 1-4 Alkyl, halogen, or hydroxyl; n is 0, 1, or 2; Each R8 is independently F or OR 8A , where each R 8A Independently hydrogen, C 1-4 Alkyl or acyl groups; Each R9 is independently a halogen, hydroxyl group, or optionally substituted C. 1-10 Alkyl or optionally substituted C 1-10 Alkoxy, where C 1-10 Alkyl or C 1-10 Each alkoxy group may be optionally substituted with one or more R groups. 9A Replace, where each R 9A Independently, it can be an amino, ester, amide, mercapto, carboxyl, cyano, halogen, hydroxyl, or optionally substituted C group. 1-4 Alkoxy, optional substituted C 1-5 Cycloalkyl or optionally substituted five-membered heterocycles, R 9A Each optional replacement is by one or more R 9B Replace, where each R 9B Independently for C 1-4 Alkyl, amino, cyano, halogen, or hydroxyl; p is 0, 1, or 2; Each R 10 Independently for R 10A -N(R) 10A (R) 10B -OR 10A -SR 10A -S(O)R 10A or -S(O)2R 10A , where R 10A C is an optional replacement 4-20 Alkyl or optionally substituted 4-20 heteroalkyl groups, Where C 4-20 Each of the alkyl or 4-20 heteroalkyl groups is optionally substituted with one or more R groups. 10C Replace, and R 10C With another R 10A Partial linkages form dimers or trimers. R 10B For hydrogen or R 10A , Each R 10C Independently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thioalkyl, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thioketone, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein X1, X2, and X3 are each independently substituted C with optional substitution. 1-4 Alkyl, optionally substituted C 1-6 Cycloalkyl, optionally substituted 5- or 6-membered heterocyclic or optionally substituted aryl, wherein C 1-4 Alkyl, C 1-6 Each optional substituent of the cycloalkyl, 5- or 6-membered heterocyclic or aryl group is replaced by one or more R groups. 10D replace, L1 and L2 are each independently optional C. 1-6 Alkyl or optionally substituted 1-10 heteroalkyl groups, wherein the C 1-6 Each optional substituent of the alkyl or 1-10 heteroalkyl group is replaced by one or more R groups. 10E replace, Each R 10D Independently for R 10E Or by one or more R 10E Optional substitution of C 1-6 alkyl, Each R 10E Independently, it is an amino, amide, azo, carbonyl, carboxyl, cyano, formyl, guanidine, halogen, hydroxyl, imide, imino, isothiocyanate, nitrile, nitro, nitroso, nitoxy, oxo, thioalkyl, sulfinyl, sulfonyl, thioaldehyde, thiocyanate, thioketone, or urea group; And m is 1, 2 or 3; The SGLT1 inhibitor compound described therein has a major pharmacological site of action in the intestine of the subject.

2. The method according to claim 1, wherein the method is used to treat GIP-dependent Cushing's syndrome, GH-secreting pituitary tumors that ectopically express GIPR, neuroendocrine tumors that ectopically express GIPR, or any organ or tissue that ectopically expresses GIPR.

3. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound is selected from: , , , , and .

4. The method according to any one of claims 1-2, wherein the pharmaceutical salt of the SGLT1 inhibitor compound is selected from the monosaccharide salt and hemifumaric acid dehydrate of the compound.

5. The method according to any one of claims 1-2, wherein the dose of the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is about 0.1 mg / day to about 60 mg / day.

6. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered once or three times daily in a single dose of about 0.1 mg to about 20 mg.

7. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered before a meal.

8. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered at a dose of 2.5 mg to 10 mg once or three times daily.

9. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered orally.

10. The method according to any one of claims 1-2, wherein the SGLT1 inhibitor compound or a pharmaceutically acceptable salt thereof is administered in an oral dosage form selected from coated capsules, coated tablets, liquids, powders, and orally disintegrating tablets.

Images